A known class of long-acting local anaesthetics comprises 1-alkyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamides. This class includes racemic bupivacaine, levobupivacaine, mepivacaine and ropivacaine. Racemic bupivacaine is widely used, and is available for both epidural and spinal administration.
The effective utility of levobupivacaine in man, in vivo, is evidenced for the first time in WO-A-9510276, WO-A-9510277 and Gristwood et al, Exp. Opin. Invest. Drugs 3(11):1209-12 (1994). The latter documents indicate the potential utility of levobupivacaine in obstetrics, in part at least because of reduced CNS side-effects.
WO 90/00390 discloses aqueous solutions for spinal analgesia, comprising dezocine, bupivacaine and also 5-10% w/v glucose if it is desired that the solution should be hyperbaric. The solutions of the Examples which are hyperbaric are also hypertonic.
Chung et al, Br. J. Anaesth. (1996) 77(2):145-9, discloses the use of hyperbaric solutions containing 0.25% w/v bupivacaine and 5% w/v glucose, for spinal anaesthesia. This was done as part of a study to determine the effect of volume of solution administered.
Hytta et al, Regionale-Anaesthesie (1982) 5:85-8, discloses the use of 0.5% bupivacaine, either "isobaric" (Marcain.RTM.) or hyperbaric (8% glucose). The former is presumably plain Marcain.RTM. which is in fact hypobaric.
In the U.S., a hyperbaric formulation of bupivacaine is available, comprising 2 ml ampoules of 0.75% bupivacaine (racemate) and 8.25% glucose. The use of 0.75% solutions of racemic bupivacaine is contra-indicated, in obstetrical anaesthesia. The Physician's Desk Reference.RTM. carries a "black box" warning.
In Europe, 4 ml ampoules are available which contain 0.5% bupivacaine and about 8% glucose. These formulations are hypertonic, having an osmolality of approximately 500 mOsm/kg.
There are certainly good reasons for including glucose. As reported by Logan et al, Brit. J. Anaesthesia (1986) 58:292-296, plain 0.5% bupivacaine has wide variability in terms of its intrathecal spread, when administered for spinal anaesthesia. A hyperbaric solution containing 8% glucose spreads rapidly but predictably; see Chambers et al, Brit. J. Anaesthesia (1981) 53:279-282.
Bannister et al, Brit. J. Anaesthesia (1990) 64:232-234, reports the effects of intrathecal injection of 0.5% bupivacaine in solutions containing 0.33%, 0.83% or 8% glucose. It is suggested that, whereas using 0.33% glucose resulted in variable blocks as seen using the plain solution, 0.83% glucose is preferable. It is reported that "Making bupivacaine slightly hyperbaric seemed to produce a predictable spinal anaesthetic"; however, formulations comprising 0.5% bupivacaine and 0.83% glucose are in fact hypobaric.
It has apparently been accepted by anaesthetists that a high concentration of glucose is necessary. This is despite the fact that such formulations have been associated with neurotoxicity.